Several cardiovascular variables are used clinically to assess the performance of the heart as an effective pump. Chief among them are the end-diastolic volume and pressure, contractility, and ejection fraction (all defined below), usually—but not limited to—those pertaining to the left ventricle.
End-diastolic volume (EDV) is the volume in the ventricle at the end of the ventricular filling period of the cardiac cycle. End-systolic volume (ESV) is the volume in the ventricle at the end of the ejection period of the cardiac cycle.
Stroke volume (SV) of the heart or of the left or right ventricle may be defined as the difference between corresponding end-systolic and end-diastolic volumes, namely:SV=EDV−ESV  (EQ. 1)
Cardiac output (CO) is the amount of blood the heart pumps out over a unit of time. Typical values of CO in resting adults range from 3 liters/minute to 6 liters/minute. One basis for estimating or measuring CO is the formula CO=HR×SV, where SV is cardiac stroke volume and HR is heart rate. If SV is measured in liters/beat and HR is measured in beats/minute, then CO is given in liters/minute, although any other units of volume and time may be used. Another basis for estimating or measuring CO is the formula CO=MAP/TPR, where MAP is mean arterial blood pressure and TPR is total peripheral resistance.
Ejection fraction (EF) is defined as the ratio of the stroke volume (SV) to the ventricular end-diastolic volume (EDV) and is expressed in percent, namely:EF=SV/EDV=(EDV−ESV)/EDV  (EQ. 2)
More simply, EF represents the percentage of the end-diastolic volume of a ventricular chamber that is ejected per beat. EF can be measured in the right ventricle (RV) or the left ventricle (LV). Thus, RVEF is right ventricular ejection fraction and LVEF is left ventricular ejection fraction.
In this application, embodiments are presented with respect to the left ventricle, for which Applicants sometimes write EF instead of LVEF. The methods and systems described herein can easily be extended to the right ventricle.
Cardiac contractility is a measure of ventricular elastance at the end of the ejection.
Chronically elevated end-diastolic pressures and volumes indicate poor pump performance, as do low states of contractility and a reduced ejection fraction [1]. (Numbers in square brackets refer to the reference list included herein. The contents of all these references are incorporated herein by reference.) Ideally, these variables should be measured non- to minimally invasively for establishing initial diagnoses and tracked continuously for monitoring of disease progression and titration of therapeutic interventions. The current clinical gold-standard measurements for measuring these variables, however, are costly, require expert operators, and are only performed intermittently
Cardiac volumes are commonly measured echocardiographically: a skilled operator performs intermittent ultrasonic evaluations of the heart during which the relevant cardiac volumes are determined. Cardiac ejection fraction is then calculated from the resultant end-systolic and end-diastolic volume estimates.
The pulmonary capillary wedge pressure is used as a surrogate for the left ventricular end-diastolic pressure (the ‘preload’ of the left ventricle). The ‘wedge pressure’ measurement is highly invasive, requiring a Swan-Ganz catheter to be advanced through the right atrium and right ventricle and placed into a main branch of the pulmonary artery. When a balloon at the catheter's tip is inflated to block flow temporarily, the pressure distal to the balloon equilibrates with the pressure at the level of the pulmonary vein. The resultant pressure is taken to be left-ventricular end-diastolic pressure. Some Swan-Ganz catheters are specially equipped with rapid-response thermistors that allow for estimation of right ventricular volumes and therefore right ventricular ejection fraction [2]. Due to its highly invasive nature, the Swan-Ganz catheter is rarely used outside the intensive care or the peri-operative care environments and even in these settings, its benefits are increasingly being questioned [5, 6].
Contractility is an important concept in cardiac physiology and clinical cardiology. Changes in cardiac contractility pertain to the heart's ability to change its systolic contractile state so as to adjust its effectiveness as a pump. Cardiac contractility, however, is never directly assessed clinically, as a direct measurement would entail acquiring ventricular volume and pressure simultaneously while rapidly varying the loading (filling) conditions of the heart. (Rapid changes in loading conditions are required such that contractility is not changed by cardiovascular reflex mechanisms during the course of the measurement.) Such a procedure requires one ventricular catheter to measure pressure, possibly a balloon catheter in the vena cava to vary the heart's loading conditions, and an accurate method to measure ventricular volume rapidly. A clinical measure of cardiac contractility is the maximum rate of change of ventricular pressure during the isovolumic contraction phase of the cardiac cycle. In the clinically more important left ventricle, such an assessment of contractility would require left-sided cardiac catheterization. This is never done routinely except possibly in patients undergoing cardiac catheterization for symptoms of shortness-of-breath or assessment of valve dysfunction.
As reported in WIPO patent application publication No. WO2007109059 to Mukkamala, the contents of which are incorporated herein in their entirety, to improve upon the significant disadvantages shared by imaging techniques, a few methods have been introduced for continuous and automatic monitoring of EF or ventricular volume. These methods include continuous thermodilution technique, the non-imaging nuclear monitor, the conductance catheter, and sonomicrometry. However, these methods are all limited in at least one clinically significant way.
The continuous thermodilution method involves automatic heating of blood in the right ventricle via a thermal filament, measurement of the temperature changes downstream in the pulmonary artery via a fast response thermistor, construction of a bolus thermodilution washout decay curve, and estimation of RVEF based on the extent of the temperature decay over a cardiac cycle. An attractive feature of this method is that it requires only a pulmonary artery catheterization, which is occasionally performed in a subset of critically ill patients (see below). As a result, the method is sometimes conducted in clinical practice, though it has not gained widespread popularity. On the other hand, the method does not provide beat-to-beat estimates of RVEF but rather estimates at time intervals of approximately a minute or more. Furthermore, the method continually perturbs the circulation and is not amenable to ambulatory or home health care monitoring, both of which could potentially reduce hospital admissions and health care costs. Perhaps the most significant limitation of this method is that it cannot be utilized to determine the more clinically relevant LVEF.
In contrast, the non-imaging nuclear monitor, the conductance catheter, and sonomicrometry do permit automatic, beat-by-beat monitoring of LVEF. However, as discussed below, the substantial limitations of each of these methods have precluded their use in clinical practice.
In non-imaging nuclear monitoring of LVEF, the patient is given an injection of a radioactive tracer, which distributes throughout the circulation. The amount of the radioactive tracer in the LV is then measured with a crystal scintillation detector attached to a single bore converging collimator. The method is able to monitor LV volume at a high temporal resolution (10 ms) by sacrificing the spatial resolution, which would otherwise be needed to produce images. An appealing feature of the method is that LVEF is estimated without any assumptions about ventricular geometry. Additionally, systems have been developed for both bedside and ambulatory monitoring. However, the method is not in clinical use because of the difficulty in positioning the detector at the appropriate location on the patient's chest and in correcting for background radioactivity originating from extra-cardiac regions. The method also has the obvious disadvantage of exposing the patient to radiation.
The conductance catheter method involves placing a multi-electrode catheter in a ventricular cavity, continually applying AC current to the electrodes to generate an electric field, measuring the resulting voltage gradients, and estimating the ventricular volume from the intra-ventricular conductance using geometric assumptions. Thus, the method is able to provide estimates of either LVEF or RVEF. However, for LVEF, the method requires a left heart catheterization, which is rarely performed in critically-ill patients. Moreover, the method is not capable of accurately estimating absolute or proportional ventricular volume, which is needed to reliably compute EF, due mainly to the parallel conductance (offset error) and non-uniformity of the generated electric field (scale factor error). Finally, another disadvantage of this method is that it is not amenable to ambulatory or home health care monitoring.
Sonomicrometry involves suturing crystals to opposite sides of the ventricular endocardium and using the ultrasound transit time principle to estimate the ventricular volume based on geometric assumptions. While the method can provide accurate estimates of either LVEF or RVEF when a sufficient number of crystals are used, it is obviously much too invasive to ever be employed in clinical practice.
It would be desirable to be able to accurately monitor beat-by-beat LVEF and/or beat-by-beat RVEF based on the mathematical analysis of continuous blood pressure. It would be desirable to be able to accurately monitor beat-by-beat EDV and/or beat-by-beat cardiac contractility based on the mathematical analysis of continuous blood pressure. Continuous blood pressure is routinely monitored in clinical practice and several systems are currently available for continuous monitoring of specifically systemic arterial blood pressure (SABP, e.g., invasive catheters, non-invasive finger-cuff photoplethysmography, non-invasive arterial tonometry, and implanted devices), LV pressure (LVP, e.g., implanted devices), pulmonary artery pressure (PAP, e.g., invasive pulmonary artery catheters and implanted devices), and RVP (e.g., invasive pulmonary artery catheters and implanted devices). Thus, in contrast to the aforementioned methods, this approach would readily permit continuous and automatic measurement of LVEF and RVEF in the context of several important clinical applications. For example, such an approach could be applied to: (1) routinely employed invasive SABP and PAP catheter systems for titrating therapy in the intensive care unit (ICU), continuous monitoring of cardiac surgery in the operating room (OR), and remote ICU monitoring; (2) implanted SABP, PAP, RVP, and LVP systems for chronic, ambulatory monitoring of cardiovascular disease and facilitating the diagnosis of ischemia with surface ECGs; and 3) non-invasive SABP systems for emergency room (ER) or home health care monitoring. Note that these clinical applications of continuous and automatic EF monitoring have, for the most part, not been realized with the currently available measurement methods. Moreover, a blood pressure-based approach could estimate EF without making any assumptions about the ventricular geometry.
In WIPO patent application publication No. WO2007109059 to Mukkamala, systems and methods for estimating EF from a central arterial blood pressure waveform are described. These systems and methods assume a particular ventricular elastance function and performing an intra-beat fit of this function to the central arterial blood pressure (cABP) waveform. The method of Mukkamala is thus still quite invasive. However, it does not require calibration against true or reference EF measurements.
Thus, methods and apparatus for effectively monitoring beat-by-beat EF, beat-by-beat EDV, and beat-by-beat contractility, are extremely desirable in that they would greatly facilitate the monitoring, diagnosis, and treatment of cardiovascular disease. In addition, if these methods and apparatus could be noninvasive or minimally-invasive, such that only a peripheral blood pressure waveform is required, they would be quite useful.
The statements in this section merely provide background information related to the present disclosure and may not constitute prior art